New research finds the Zika virus can infect neural cells crucial for brain development in embryos, suggesting a potential biological explanation for the cases of microcephaly seen in Latin America during the Zika outbreak. Researchers derived progenitor cells which go on to form neurons in the cortex from induced pluripotent stem cells (iPSCs), and found that the Zika virus easily infected the progenitor cells in the lab. Infected cells were more likely to die and less likely to divide normally. The research is published in Cell Stem Cell.
Dr. Amelia Pinto, Assistant Professor, Department of Molecular Microbiology & Immunology, Saint Louis University (webpage):
Expertise: Understanding the immune response to arboviruses including West Nile, chikungunya, Zika, and dengue.
“By determining whether Zika virus infects cells in the brain and what happens to a cell that is infected, this paper begins to tackle questions surrounding how a virus that had previously been known to cause a mild illness could be linked to microcephaly. The authors of this paper show that Zika virus can infect a human neural progenitor cell (hNPC), which is similar to human cortical neurons. The authors go onto show that Zika infection ‘increases cell death and dysregulates cell cycle progression’ in the hNPCs.
“The questions we must ask are: ‘How relevant is this cell based model for studying human Zika virus infection?’ and ‘How do we make the jump in understanding virus infection in culture to a cause of microcephaly?’ The short answer is that this study is just the beginning, and many more studies are needed to understand the relationship between Zika and microcephaly.
“The model is not without some problems. The hNPCs are only similar (not the same) to cells in the brain, therefore how Zika actually acts in the brain might be different to what this model suggests. Another problem surrounds the association of Zika infection of hNPCs with microcephaly. Many viruses can infect neuronal cells, including the closely related West Nile virus, and these viruses are not associated with microcephaly, so arguing for a link between neuronal cell infection and microcephaly may be premature.
“What this paper does is what we all hope to achieve; it allows us to ask more questions and perhaps with further study of these Zika infected hNPCs we will gain insight into this re-emerging pathogen.”
Dr. Sika Zheng, Assistant Professor of Biomedical Sciences, University of California, Riverside (webpage):
Expertise: The activity, mechanism, function and dysfunction of gene regulation at the RNA level in the brain.
“In the midst of Zika virus outbreak this is a timely report in searching for directions of targeted therapy.
“Neural progenitors are the parental cells of neurons and glias, two major cell types in the brain. During embryonic development, most neural progenitors undergo cell division generating two daughter cells. One maintains the proliferating ability of progenitors, whereas the other gives rise to a neuron or glia. Deficiency in progenitor cell pools is widely associated with and is believed to contribute to microcephaly. Some viruses, e.g. HIV, can cause microcephaly while affecting progenitors.
“The higher infection rate of progenitors by Zika virus and subsequent abnormality as shown by Tang et al., albeit in vitro, points toward a possible causative link between Zika virus and microcephaly. Much more work can strengthen this observation, in particular examining the relationship of relevant virus doses and the degrees of progenitor cell death as well as proliferating and differentiating capacity of the infected progenitors.
“Ultimately, in vivo studies will be needed to confirm a central role of progenitors in bridging virus infection and microcephaly. One key question is whether direct infection of progenitors is necessary to cause microcephaly. Could immune responses and virus associated proteins also play some pathogenic roles? These obvious next steps, if mirroring the in vitro observations, will be a giant leap toward using progenitor cells as a tractable system to develop therapies.”
Dr. Alyssa Stephenson-Famy, Assistant Professor, Department of Obstetrics and Gynecology, University of Washington (website):
Expertise: Maternal fetal medicine, maternal medical disorders in pregnancy.
“This is exactly the kind of research that we need to demonstrate a causative link and mechanism between the Zika virus and microcephaly. Although we also need more confirmatory epidemiologic data now from Zika endemic areas, the model in this study demonstrates that Zika readily infects forebrain-specific human neural progenitor cells (hNPCs) in vitro. The decrease in number of viable hNPCs in Zika infected cultures, potentially due to increase in cell death and cell cycle dysregulation, certainly suggests a mechanism by which Zika could cause the microcephaly phenotype that we are seeing in babies.”
Dr. Flora Vaccarino, Harris Professor, Child Study Center and Department of Neurobiology, Yale University (webpage):
Expertise: Neural stem cells; cerebral cortex; neuronal progenitors; postmortem human brain; induced pluripotent stem cells.
“The study is obviously very important because we don’t know for sure whether Zika virus can infect brain cells, and what type of brain cells in particular. The question the authors address is: can the virus directly infect brain cells as opposed to indirectly affecting the growth of the brain by infecting other tissues that are important for brain development, like the placenta or vasculature?
“Taken at face value, this study seems to show that neural progenitor cells, which mature into neural cells during brain development, are infected by a low rate of exposure to the Zika virus. The authors show that the progenitor cells they derive from induced pluripotent stem cells (iPSCs) have a higher infection rate than either iPSCs or neurons. Their data also suggests the ability of the progenitor cells to divide and proliferate are particularly affected, which goes along with microcephaly.
“Unfortunately, the authors don’t describe what method they use to generate the neural progenitor cells from iPSCs. It’s crucial to understand if the cells are genuine neural progenitors, and the approximate stage of development. I’m prepared to believe they are, as their methods appear to be standard, but perhaps gene expression analyses in a few more lines would have been more convincing.
“Since the cells are derived from iPSCs it’s still not certain that neural progenitor cells can definitely be infected by the Zika virus, and the link between Zika and microcephaly is also still not certain. We need to wait for post mortem tissue samples from a fetus that has been infected. The authors could also have used primary human progenitors (not iPSC derived) and infected them in vitro to be 100% sure. Once you’ve established that neural progenitors can definitely be infected, you could then use iPSCs to investigate exactly what happens after infection. You would want to know how does the virus get in, what does it bind to, and what does it do to the cells? That would be valuable because it could lead to potential treatments.”
Dr. Sue O’Shea, Professor of Cell and Developmental Biology, University of Michigan (webpage):
Expertise: Using human stem cells grown in culture to study cell-to-cell communication that occurs during formation of the nervous system.
“This work is important in that it clearly demonstrates that Zika virus preferentially infects human neural precursor cells, rather than pluripotent stem cells or more mature neurons, and that infected progenitor cells release viral particles. Assuming that microcephaly is a result of either increased cell death, decreased cell proliferation or inhibition of cell migrations to the cortex, the work also illustrates that there is increased cell death as well as changes in cell cycle. Further research looking at cell migration, assessments of whether the same effects are seen for different strains of the Zika virus, and how the virus crosses the blood brain barrier should follow.”
Dr. Mark Schleiss, Professor of Pediatrics and Director of Division of Infectious Disease and Immunology, University of Minnesota (webpage):
Expertise: Pediatric infectious diseases; viral infections; molecular virology. Dr Schleiss studies cytomegalovirus, another virus known to cause microcephaly.
“I think this is a big step in the right direction in terms of understanding the pathogenesis of Zika. Recent papers have found virus particles in fetal brain tissue and amniotic fluid, so as the scientific data has emerged most scientists have not had any doubt that the Zika virus is responsible for the brain injury. But as the Zika virus story has unfolded there has been speculation about the mechanism, which this study addresses.
“The major contribution of this paper is that it shows the cells support something called lytic infection, which means that the virus infects the cell and the cell dies after the virus has replicated. The paper also indicates that virus infection modifies the cell’s gene expression, affecting the life cycle of the cell.
“Neural progenitor cells differentiate into the brain as we know it. They are preprogrammed to go down developmental pathways which lead to mature neurons. The development of the brain in the fetus is an amazingly complex process that involves something called neuronal migration. You begin with this collection of pluripotent cells which move through the brain establishing connections and structure. A normal brain has a convoluted structure. So a smooth brain without those convolutions, as seen with Zika, shows abnormality in neuronal migration and a loss of brain cells.
“The evidence for direct viral infection of the brain cells is overwhelming, and the downstream effects of the microcephaly are surely related to not only the death of the cells but also the disruption of the normal developmental blueprint that sculpts and shapes the brain.
“Like all good science this paper raises as many questions as it answers. Additional evidence to confirm the findings would come from in vitro modeling with human fetal brain tissue. While human fetal tissue research is becoming increasingly difficult to do, directly studying fetal brain tissues would be desirable if the social and political climate permitted it.”
Declared interests (see GENeS register of interests policy):
Dr. Sue O’Shea: “We have a collaborative U19 grant with the research group at Johns Hopkins”.
No further interests declared
‘Zika Virus Infects Human Cortical Neural Precursors and Attenuates Their Growth‘ by Tang et al., published in Cell Stem Cell on Friday 4 March, 2016.